The present invention relates to the indication of early phases of potentially catastrophic illnesses and relates to heart rate variability monitoring in patients. In particular, the present invention relates to methods and apparatus for early detection of potentially catastrophic illnesses in a patient.
Approximately 40,000 very low birth weight (xe2x80x9cVLBWxe2x80x9d) infants (less than 1,500 gm) are born in the United States each year. Ventura et al., xe2x80x9cAdvance Report of Final Natality Statistics, 1994,xe2x80x9d Monthly Vital Statistics Report; 44, pp. 1-88 (1996). Survival of this group has improved with advances in neonatal intensive care, but late-onset sepsis and necrotizing enterocolitis (xe2x80x9cNECxe2x80x9d) continue to be major causes of morbidity and mortality. Stoll B. J., Gordon T., Korones S. B., Shankaran S., Tyson J. E., Bauer C. R., xe2x80x9cLate-onset Sepsis in Very Low Birth Weight Neonates: A Report from the National Institute of Child Health and Human Development Neonatal Research Network,xe2x80x9d Journal of Pediatrics; 129:63-71 (1996); Gray J. E., Richardson D. K., McCormick M. C., Goldmann D. A., xe2x80x9cCoagulase-Negative Staphylococcal Bacteremia Among Very Low Birth Weight Infants: Relation to Admission Illness Severity, Resource Use, and Outcome,xe2x80x9d Pediatrics, 95:225-230 (1995). Unfortunately these illnesses are common in neonates, and infected infants have a significant increase in the number of days spent on the ventilator and an average increase in duration of hospital stay of 25 days. See Stoll et al. above.
Neonatal sepsis occurs in as many as 25% of infants weighing less than 1,500 gm at birth, and the rate is about 1 per 100 patient days. Gladstone, I. M., R. A. Ehrenkrantz, S. C. Edberg, and R. S. Baltimore, xe2x80x9cA Ten-Year Review of Neonatal Sepsis and Comparison with the Previous Fifty Year Experience,xe2x80x9d Pediatric Infectious Disease Journal; 9:819-825 (1990); Moro, M. L., A. DeToni, I. Stolfi, M. P. Carrieri, M. Braga, and C. Zunin, xe2x80x9cRisk Factors for Nosocomial Sepsis in Newborn Infants and Intermediate Care Units,xe2x80x9d European Journal of Pediatrics; 155:315-322 (1996). The National Institute of Child Health and Human Development (xe2x80x9cNICHDxe2x80x9d) Neonatal Research Network found that neonates who develop late-onset sepsis have a 17% mortality rate, more than twice the 7% mortality rate of noninfected infants.
Risk factors for late-onset sepsis are ubiquitous in the neonatal intensive care unit (xe2x80x9cNICUxe2x80x9d): intubation, umbilical catheters, prolonged mechanical ventilation, low birth weight, parenteral nutrition via central venous catheters, respiratory distress syndrome, bronchopulmonary dysplasia, severe intraventricular hemorrhage, and nasogastric and tracheal cannulae are all independently associated with sepsis. See Moro et al. supra. Each interventional device represents a potential source of infection and increases the risk of catastrophic infectious illness. Id.
Necrotizing enterocolitis affects up to 4,000 infants in the U.S. yearly, and an estimated 10 to 50% of infants who develop NEC die. Neu, J., xe2x80x9cNecrotizing Enterocolitis,xe2x80x9d Pediatric Clinics of North America 43:409-432 (1996). Infants who develop NEC often require intubation and an increase in respiratory support. Survivors are often left with strictures and short-bowel syndrome.
Unfortunately, prior to the discovery of the present invention there has been no reliable clinical means for early diagnosis of these diseases. Clinical neonatologists caring for these VLBW infants recognize sepsis and NEC as potentially catastrophic illnesses, and thus do not hesitate to obtain blood cultures and administer antibiotics empirically at the first appearance of symptoms in an attempt to avert disaster. Likewise, physicians do not hesitate to stop feeding and obtain radiographic studies should any abdominal finding occur. Early diagnosis of neonatal sepsis is difficult (Escobar, G. J, xe2x80x9cThe Neonatal xe2x80x9cSepsis Work-upxe2x80x9d: Personal Reflections on the Development of an Evidence-Based Approach Toward Newborn Infections in a Managed Care Organization,xe2x80x9d Pediatrics, 103:360-373 (1999)), as the clinical signs are neither uniform nor specific. Because of this, there are many unnecessary blood cultures, many unnecessary administration of short courses of antibiotics to infants without bacterial infection, and many unnecessary interruptions in neonatal nutrition. Moreover, despite these practices, sepsis and necrotizing enterocolitis continue to occur and continue to cause neonatal deaths. Indeed, by the time clinical signs and symptoms for either sepsis or NEC have developed, the illness may have progressed to an irreversible stage.
In addition, not all patients with clinical signs of sepsis have positive blood cultures. While the blood culture is felt to be the gold standard for establishing the diagnosis of sepsis due to systemic bacterial infection, there are concerns regarding its reliability (Kaftan, H. and J. S. Kinney, xe2x80x9cEarly Onset Neonatal Bacterial Infections,xe2x80x9d Seminars in Perinatology, 22:15-24 (1998)), especially if single samples of small volume are submitted (Aronson, M. D. and D. H. Bor, xe2x80x9cBlood Cultures,xe2x80x9d Ann. Intern. Med., 106:246-253 (1987); Kellogg, J. A., F. L. Ferrentino, M. H. Goodstein, J. Liss, Shapiro, S L, and D. A. Bankert, xe2x80x9cFrequency of Low Level Bacteremia in Infants from Birth to Two Months of Age,xe2x80x9d Pediatric Infectious Disease Journal, 16:381-385 (1997)), as is often the practice in critically ill newborn infants. For example, as many as 60% of culture results may be falsely negative if only 0.5 mL blood is obtained from infants with low-colony-count sepsis. Schelonka, R. L., M. K. Chai, B. A. Yoder, D. Hensley, R. M. Brockett, and D. P. Ascher, xe2x80x9cVolume of Blood Required to Detect Common Neonatal Pathogens,xe2x80x9d J. Pediatr., 129:275-278 (1996). In a study of 298 aerobic culture specimens, the mean blood volume submitted was 0.53 mL and 55% of samples contained less than 0.5 mL. Neal, P. R., M. B. Kleiman, J. K. Reynolds, S. D. Allen, J. A. Lemons, and P. L. Yu, xe2x80x9cVolume of Blood Submitted for Culture from Neonates,xe2x80x9d Journal of Clinical Microbiology, 24:353-356 (1986). It is suspected that 30-40% of all infants with sepsis have negative blood cultures. For example, in two studies, approximately 20% of infants with infection proven by post-mortem cultures and autopsy were not so identified using pre-mortem blood cultures (Pierce, J. R., G. B. Merenstein, and J. T. Stocker, xe2x80x9cImmediate Postmortem Cultures in an Intensive Care Nursery,xe2x80x9d Pediatric Infectious Disease, 3:510-513 (1984); Squire, E., B. Favara, and J. Todd, xe2x80x9cDiagnosis of Neonatal Bacterial Infection: Hematologic and Pathologic Findings in Fatal and Nonfatal Cases,xe2x80x9d Pediatrics, 64:60-64 (1970)).
The current hypothesis is that the clinical syndrome of sepsis is brought about by the host response as a response to insults such as bacterial infection. The major host response is the release of cytokines, small circulating peptides that serve as mediators of the inflammatory response. The syndrome common to sepsis and sepsis-like illness has been named the Systemic Inflammatory Response Syndrome (SIRS) (Members of the ACCP/SCCM Consensus Conference Committee, xe2x80x9cAmerican College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Definitions for Sepsis and Organ Failure and Guidelines for the Use of Innovative Therapies in Sepsis,xe2x80x9d Critical Care Medicine, 20:864-874 (1992)), and the pathogenesis suggested to be an imbalance between pro-inflammatory and anti-inflammatory effects of cytokines. Bone, R. C., C. J. Grodzin, and R. A. Balk, xe2x80x9cSepsis: a New Hypothesis for Pathogenesis of the Disease Process,xe2x80x9d Chest, 112:235-243 (1997). In sepsis and sepsis-like illness, circulating cytokines play a major role in initiating and maintaining the inflammatory response, and cytokine levels correlate with the severity of illness. Anderson, M. R. and J. L. Blumer, xe2x80x9cAdvances in the Therapy for Sepsis in Children,xe2x80x9d Pediatric Clinics of North America, 44:179-205 (1997); Harris, M. C., A. T. J. Costarino, J. S. Sullivan, S. Dulkerian, L. McCawley, L. Corcoran, S. Butler, and L. Kilpatrick, xe2x80x9cCytokine Elevations in Critically Ill Infants with Sepsis and Necrotizing Enterocolitis,xe2x80x9d J. Pediatr., 124:105-111 (1994); Glauser, M. P., D. Heumann, J. D. Baumgartner, and J. Cohen, xe2x80x9cPathogenesis and Potential Strategies for Prevention and Treatment of Septic Shock: an Update,xe2x80x9d Clinical Infectious Diseases,xe2x80x9d 18:S205-S216 (1994). Kuster and colleagues have recently found elevated levels of circulating cytokines for up to two days prior to the clinical diagnosis of clinical sepsis. Kuster, H., M. Weiss, A. E. Willeitner, S. Detlefsen, I. Jeremias, J. Zbojan, R. Geiger, G. Lipowsky, and G. Simbruner, xe2x80x9cInterleukin-1 Receptor Antagonist and Interleukin-6 for Early Diagnosis of Neonatal Sepsis 2 Days Before Clinical Manifestation,xe2x80x9d Lancet, 352:1271-1277 (1998). Cytokines have widespread effects on signal transduction processes and may interfere with normal events of Heartrate (xe2x80x9cHRxe2x80x9d) control by the sympathetic and parasympathetic nervous systems. For example, the cytokines TNF-xcex1, IL-1xcex2 and IL-6 increase HR, but they blunt HR responses to xcex2-adrenergic agonists. Oddis, C. V. and M. S. Finkel, xe2x80x9cCytokines and Nitric Oxide Synthase Inhibitor as Mediators of Adrenergic Refractoriness in Cardiac Myocytes,xe2x80x9d European Journal of Pharmacology, 320:167-174 (1997); Oddis, C. V., R. L. Simmons, B. G. Hattler, and M. S. Finkel, xe2x80x9cChronotropic Effects of Cytokines and the Nitric Oxide Synthase Inhibitor, L-NMMA, on Cardiac Myocytes,xe2x80x9d Biochemical and Biophysical Research Communications, 205:992-997 (1994). In addition, sepsis and sepsis-like illness are associated with alterations in beta-adrenergic receptor number and distribution, (Tang, C., J. Yang, and M. S. Liu, xe2x80x9cProgressive Internalization of Beta-Adrenoceptors in the Rat Liver During Different Phases of Sepsis,xe2x80x9d Biochimica et Biophysica Acta, 1407:225-233 (1998); Hahn, P. Y., P. Yoo, Z. F. Ba, I. H. Chaudry, and P. Wang, xe2x80x9cUpregulation of Kupffer Cell Beta-Adrenoceptors and cAMP Levels During the Late Stage of Sepsis,xe2x80x9d Biochimica et Biophysica Acta, 1404:377-384(1998)) and with multiple steps of signal transduction via b-adrenergic receptors. Bernardin, G., A. D. Strosberg, A. Bernard, M. Mattei, and S. Marullo, xe2x80x9cBeta-Adrenergic Receptor-Dependent and -Independent Stimulation of Adenylate Cyclase Is Impaired During Severe Sepsis in Humans,xe2x80x9d Intensive Care Medicine, 24:1315-1322 (1998).
Clinicians have found no clinical signs or laboratory test findings to be reliable for very early diagnosis of neonatal sepsis. In fact, 10 to 20 infants are treated for sepsis for every one infant that has a positive blood culture. Gerdes, J. S. and R. A. Polin, xe2x80x9cSepsis Screen in Neonates with Evaluation of Plasma Fibronectin,xe2x80x9d Pediatric Infectious Disease Journal, 6:443-446 (1987). Thus, a successful surveillance strategy which leads to an earlier diagnosis of potentially catastrophic illnesses such as sepsis and NEC as well as non-infectious illnesses in neonates and premature newborns is necessary and critical in decreasing mortality and morbidity. Moreover, such a surveillance strategy is also useful for detecting potentially catastrophic illnesses in other patients, including infants, toddlers, young children, adolescents and adults. The present invention provides such surveillance strategies. Using the novel surveillance strategies of the present invention, the inventors have found that abrupt clinical deteriorations that prompted physicians to obtain blood cultures and start antibiotics were proceeded for up to 24 hours by increasing abnormal heart rate characteristics xe2x80x9cHRCxe2x80x9d of reduced baseline variability and sub-clinical, short-lived decelerations in HR, and by increasingly abnormal Score for Neonatal Acute Physiology xe2x80x9cSNAPxe2x80x9d scores.
Heretofore, heart rate variability (xe2x80x9cHRVxe2x80x9d) measurement has been used as a means of assigning long-term prognosis, usually in adults with heart disease. Additionally, since it is known that HRV is abnormal during illness, physicians have traditionally measured HRV as an indication of such illnesses. For example, in healthy newborn infants, time series of heart period (or RR intervals, the time between successive heart beats) show obvious variability. Numerous publications are available which detail the measurement and characterization of such heart rate variability. See, e.g., Ori, Z., G. Monir, J. Weiss, X. Sayhouni, and D. H. Singer, xe2x80x9cHeart Rate Variability: Frequency Domain Analysis,xe2x80x9d Cardiology Clinics 10:499-533 (1992); Kleiger, R. E., P. K. Stein, M. S. Bosner, and J. N. Rottman, xe2x80x9cTime Domain Measurements of Heart Rate Variability,xe2x80x9d Cardiology Clinics 10:487-498 (1992).
HRV arises from the interplay of the sympathetic and parasympathetic arms of the autonomic nervous system, which act respectively to speed or slow the heart rate. In newborn infants, as in adults, HRV is substantially reduced during severe illness. Burnard, E. D., xe2x80x9cChanges in Heart Size in the Dyspnoeic Newborn Infant.xe2x80x9d Brit Med J 1:1495-1500 (1959); Rudolph, A. J., C. Vallbona, and M. M. Desmond, xe2x80x9cCardiodynamic Studies in the Newborn, III. Heart Rate Patterns in Infants with Idiopathic Respiratory Distress Syndrome,xe2x80x9d Pediatrics 36:551-559 (1965); Cabal, L. A., B. Siassi, B. Zanini, J. E. Hodgman, and E. E. Hon, xe2x80x9cFactors Affecting Heart Rate Variability in Preterm Infants,xe2x80x9d Pediatrics 65:50-56 (1980); Griffin, M. P., D. F. Scollan, and J. R. Moorman, xe2x80x9cThe Dynamic Range of Neonatal Heart Rate Variability,xe2x80x9d J Cardiovasc. Electrophysiol 5:112-124 (1994).
These measurements, however, typically involve only a single measurement of HRV and do not include multivariable logistic regression analysis or other mulitvariable predictive statistical models. In addition, these conventional measures of HRV fail to detect abnormal HRV in patients because the measurements, such as standard deviation and power are optimized only to detect low variability. Some types of abnormal HRV patterns do not have low variability and must be detected using other kinds of measures. The present invention overcomes the deficiencies in conventional HRV measurements, and thus is useful as a means of early diagnosis of potentially catastrophic illnesses such as sepsis and necrotizing enterocolitis. These novel measures thus serve to quantify well-established markers of early fetal and neonatal distress, and they add to clinical observations by detecting sub-clinical changes in HRC.
In addition, the new measures have the advantage of reliability in data sets with missed beats, unlike conventional frequency domain measures of heart rate time series. (Bemtson, G. G. and J. R. Stowell, xe2x80x9cECG Artifacts and Heart Period Variability: Don""t Miss a Beat,xe2x80x9d Psychophysiol, 35:127-132 (1998).; Schechtman, V. L., K. A. Kluge, and R. M. Harper, xe2x80x9cTime Domain System for Assessing Variations in Heart Rate,xe2x80x9d Med Biol. Eng. Comp., 26:367-373 (1988)).